Supravalvular aortic stenosis (SVAS) is an inherited disorder that causes hemodynamically significant narrowing of the ascending aorta and other elastic arteries. SVAS can be inherited as an isolated trait or as part of the Williams syndrome (WS), a developmental disorder that results in mental retardation, premature aging of the skin and additional disorders of the extracellular matrix. Our preliminary studies strongly suggest that SVAS and WS develop because of abnormalities in elastin. First, elastin is completely linked to the SVAS phenotype in two families. Second, elastin is located on chromosome 7q11, the site of a SVAS- associated translocation. third, elastic defines anomalous BamH I, EcoR V, Hind III, Not I, and Mlu I restriction fragments in DNAs extracted from affected members of the translocation family. Fourth, SVAS and WS both cosegregate with elastin polymorphisms in one family. Finally, abnormal function of elastin could explain the pathologic features of both disorders. To determine if elastin is the SVAS gene we will use elastin cDNA and genomic clones to screen DNAs from patients for anomalous restriction fragments on pulsed field and Southern filters. Initially we will define the breakpoint of the 6p21/7q11 translocation as this rearrangement probably disrupts the SVAS gene. Once identified, we will clone and sequence the breakpoint. We will also screen for SVAS-associated rearrangements in other families and sporadic cases. Proof that elastin is the disease gene will be achieved by identifying mutations that cosegregate with the disease in families and by identifying de novo mutations in sporadic cases. Mutations will be identified using pulsed field gel electrophoresis (PFGE), Southern analyses, single-strand conformation polymorphism analyses (SSCP), RNase protection assays and sequencing. To test the hypothesis that SVAS and WS are allelic disorders, we will screen for mutations in DNAs extracted from WS patients. If these disorders are allelic, new testable hypotheses will be generated to explain the developmental abnormalities that characterize WS. To define the spectrum of mutations that cause SVAS and WS, we will continue mutational analyses in additional families and sporadic cases. The relationship between phenotype and genotype will be assessed by correlating the severity and extent of clinical features in patients with specific mutations or classes of mutations. These experiments will improve presymptomatic diagnosis of SVAS and WS and begin to unravel the pathogenic mechanisms underlying these disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathobiochemistry Study Section (PBC)
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University of Utah
Schools of Medicine
Salt Lake City
United States
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